Process of preparing delta4,6-3-ketosteroids



United Sttes Pa em 2,739,974 PROCESF; F PREPARING A -3-KET0STER0IDSFrank B. ColtonQChicago, 111.,

signments, to G. D. Searle & poration of Delaware No Drawing.Application April 6, 1953, Serial No. 347,171

assignor, by mesne as- Co., Skokie, 11]., a cor- 4 Claims.

The present invention relates to ta'new method of dehydrogenation ofsteroids and, specifically,

unsaturated steroid containing an oxygen= attached to carbon-3 withmanganese dioxide. This processof'de- In these formulae, R represents amember of the class to a'j proce'ss. "ofpreparing 'A -3-ketoster0ids'by' treatment 'o'fa monoconsisting of hydrogen and methyl, X is amember of the class consisting of hydrogen, hydroxyl, lower alkoxy and(lower alkyl)-COO-radicals and Y is a member of the class consisting ofhydrogen, acetyl, glycolyl, dihydroxyethyl and lower alkyl radicals.

Among the compounds which are useful as starting materials in the aboveprocess are such monounsaturated steroids as testosterone,l9-nortestosterone, l7-methyltestosterone, l7-ethyltestosterone, A-androstene-3,l7- diol, l7-hydroxy-2l-desoxy-corticosterone,17,20,21-trihydroxy-A -pregnene-3-one, progesterone, as well as the 17-and 21-ethers and esters thereof, such as the methyl ethers, ethylethers, benzyl ethers, acetates, propionates, benzoates and the like. Itis a special advantage of my invention that the oxygenated functions inthe radicals X and Y are not affected by this process.

This dehydrogenation process is carried out by heating themonounsaturated steroidal starting material with a large excess ofreprecipitated manganese dioxide at a temperature of about 55-150 C. inan organic solvent, filtering and concentration of the filtrate toobtain the M -ketosteroid. A great variety of organic solvents issuitable for this process, so long as the boiling point is notsubstantially below C. The reaction is conveniently carried out at therefluxing temperature of such solvents as the lower aromatichydrocarbons such as benzene, toluene and xylene, halogenatedhydrocarbons 2,739,974 tBatented Mar. 27, 1956 as d-ichloro'methane,"andlower alkanones such' as acetone and butanone.

The d diunsaturated" 3 ketosteroids have valuable androgenic, progestational and 'adrenocortic'oid properties. They are also valuable"intermediates 'in theorganic synthesis of 7-enol estersvandaethers,which can be used in the synthesis of ll-hydroxysteroids by methodspublishe'd-inthe'recent literatu'reon theisynth'e'sis of adreno-"cortical substances; 10

used in the invention is not -to'be' construedaslimitedithereby'inspirit or in scope. 'lt"'will be fapparent to those skilled inithe "artth'atmanymodifications in'nrethods and materials The examples belowillustratein detail the procedure practice of'thisiitvention. However,the

may be practiced without departing from the invention. Temperatures aregiven inde'grees centigrade C.) and relative r amounts 1 oi materialsimparts by'weig'ht.

Example] A mixture of '75 parts of'testo'sterone, '800 parts offreshlyprepared manganese dioxide and 5300' pa"rts of benzene is heatedat refluxing temperature for minutes, cooled and filtered. The filtrateis concentrated z onrthetsteamzbath and1fthe=firesidue .is' crystallized:from acetone andcwateriand:rthen.from:ether.

r A -androstadien-ryone 'th'us 1 obtained. 181-485? :C.. Aftercrystallization from ethyl acetate The .17-hydroxymelts: at aboutth'eaproduct .rneltssat 1 2094211 (3. s: ultraviolet absorption spectrumishows a maximum' at about 285. millimicrons with a molecular extinctioncoeflicient of 29000.

-'l he same .iproductis'iobtainedtwheman:equal amount of A-androstene-3,l7-diol is substituted for the-testosterone.

Example 2 Qthe l7-acetoxy A f andro'stadien-3one, melting at about I30133"C. Repeatedrecrystallization from acetone *andhex'a'ne'raisesthemeltingpointtoabout 142-144 C.

Example 3 A stirred mixture of 5 parts of testosterone propionatc, partsof manganese dioxide and 600 parts of toluene is heated at reflux for150 minutes, cooled and filtered. Upon evaporation of the solvent thel7-propionoxy-A androstadien-3-one is obtained as an oil. Chromatographyas in the preceding example and recrystallization from benzene yieldscrystals melting at about -133 C.

Example 4 A stirred mixture of 10 parts of l7-benzoyloxy-Aandrostene-3-ol, 100 parts of manganese dioxide and 1300 parts oftoluene is heated at reflux for 3 hours, cooled and filtered. Thefiltrate is evaporated to yield the 17-benzoyloxy-A -androstadien-3-one,which melts at about 251-252" C.

Example 5 A mixture of 15 parts of 19-nortestosterone, parts ofmanganese dioxide and 1000 parts of benzene is refluxed for 3 hours andworked up as in Example 1 to yield l7-hydroxy-A -estradien-3-one, whichhas an ultraviolet absorption maximum at 284 millimicrons with anextinction coeificient of 29,000.

3 Example 6 A stirred mixture of lq'parts of progesterone, 100

parts of manganese dioxide and 6000 parts of toluene is refluxed for 90minutes and then worked up as in Example 1 to yield A-pregnadien-3,20-dione. The same product melting at about 145-147" C. oncrystallization from hexane is obtained by the identical treatment of3-hydroxy-A -pregnene-20-one.

Example 7 A solution of 10 parts of l7-ethyltestosterone in 600 parts ofbutanone is stirred with 80 parts of manganese dioxide and refluxed for2 hours. Workup as in Example 1 yields 17 ethyl 17 hydroxyA-androstadien-S-one, which has an ultraviolet absorption maximum at 285millimicrons;

Example 9 A solution of 20 parts of desoxycorticosterone acetate in 2500parts of benzene is stirred and refluxed with 150 parts of manganesedioxide for 90 minutes. Workup by the procedure of Example 2 andcrystallization from an acetone-hexane mixture yields 2l-acetoxy-A-pregnadien-3,20-dione melting at about 115-117" C.

I claim:

1. The process of preparing a A -3-ketosteroid of the structural formulawherein R is a member of the class consisting of hydrogen and methylradicals, X is a member of the class consisting of hydrogen, hydroxyl,benzoyloxy and (lower alkyl)- COO-radicals and Y is a member of theclass consisting of hydrogen, lower alkyl radicals containing no morethan 2 carbon atoms, acetyl, glycolyl and dihydroxyethyl radicals, whichcomprises heating with manganese dioxide in an organic solvent acompound of the structural formula 2. The process of preparing17-hydroxy-A -androstadien-3-one which comprises heating testosterone inan organic solvent with manganese dioxide.

3. The process of preparing A -pregnadien-3,ZO-dione which comprisesheating progesterone in an organic solvent with manganese dioxide.

4. The process of preparing a compound of the structural formula 25 CH:-0 0 C-(lower alkyl) which comprises heating a compound of thestructural formula H CH: --0 0C-(1ower alkyl) in an organic solvent withmanganese dioxide.

No references cited.

1. THE PROCESS OF PREPARING A $4,6-3-KETOSTEROID OF THE STRUCTURALFORMULA